Robust network topologies for generating oscillations with temperature-independent periods.

Nearly all living systems feature a temperature-independent oscillation period in circadian clocks. This ubiquitous property occurs at the system level and is rooted in the network architecture of the clock machinery. To investigate the mechanism of this prominent property of the circadian clock and provide general guidance for generating robust genetic oscillators with temperature-compensated oscillations, we theoretically explored the design principle and core network topologies preferred by oscillations with a temperature-independent period. By enumerating all topologies of genetic regulatory circuits with three genes, we obtained four network motifs, namely, a delayed negative feedback oscillator, repressilator, activator-inhibitor oscillator and substrate-depletion oscillator; hybrids of these motifs constitute the vast majority of target network topologies. These motifs are biased in their capacities for achieving oscillations and the temperature sensitivity of the period. The delayed negative feedback oscillator and repressilator are more robust for oscillations, whereas the activator-inhibitor and substrate-depletion oscillators are superior for maintaining a temperature-independent oscillation period. These results suggest that thermally robust oscillation can be more plausibly achieved by hybridizing these two categories of network motifs. Antagonistic balance and temperature insulation mechanisms for achieving temperature compensation are typically found in these topologies with temperature robustness. In the temperature insulation approach, the oscillation period relies on very few parameters, and these parameters are influenced only slightly by temperature. This approach prevents the temperature from affecting the oscillation period and generates circadian rhythms that are robust against environmental perturbations.